title: Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models.
abstract: The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.
authors.affiliation: Pfizer Inc, San Diego, CA, USA. achim.h.krauss@gsk.com
authors.forename: Achim H P
authors.initials: AH
authors.lastname: Krauss
authors.forename: Francesco
authors.initials: F
authors.lastname: Impagnatiello
authors.forename: Carol B
authors.initials: CB
authors.lastname: Toris
authors.forename: David C
authors.initials: DC
authors.lastname: Gale
authors.forename: Ganesh
authors.initials: G
authors.lastname: Prasanna
authors.forename: Valentina
authors.initials: V
authors.lastname: Borghi
authors.forename: Valerio
authors.initials: V
authors.lastname: Chiroli
authors.forename: Wesley K M
authors.initials: WK
authors.lastname: Chong
authors.forename: Samantha T
authors.initials: ST
authors.lastname: Carreiro
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001082:Aqueous Humor / Q000201:enzymology; D002460:Cell Line; D002924:Ciliary Body / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D015237:Dinoprost / Q000819:agonists*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D007498:Iris / Q000378:metabolism; D000077338:Latanoprost; D008252:Macaca fascicularis; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014065:Tonometry, Ocular
chemical_list: D000959:Antihypertensive Agents; C568859:BOL 303259-X; D020030:Nitric Oxide Donors; D011461:Prostaglandins F, Synthetic; D009569:Nitric Oxide; D000077338:Latanoprost; D015237:Dinoprost; D006162:Guanylate Cyclase; D006152:Cyclic GMP